tbuckley/cabot-search huggingface dataset:
The PROTAC selectively degrading Bcl-x<sub>L</sub> represents a novel Hedgehog pathway inhibitor with capacity of combating resistance to Smoothened inhibitors while sparing bone growth
Authors: Shaoqing Zhang, Yue Chen, Zhongli Xu, Jun Yang, Renhong Sun, Juan Wang, Yiming Sun, Biao Jiang, Xiaobao Yang, Wenfu Tan
Journal: Theranostics (2022)

Rationale: Primary and acquired resistance to Smoothened (Smo) inhibitors largely hampered their clinical efficacy.Given the important functions of hedgehog (Hh) pathway in bone formation and development, the permanent defects in bone growth caused by Smo inhibitors further restrict the use of Smo inhibitors for pediatric tumor patients.Anti-apoptotic Bcl-2 proteins regulate Hh activity by engaging a Bcl-2 homology (BH) domain sequence found in suppressor of fused (Sufu).In this study, we tested the effect of SIAIS361034, a Proteolysis Targeting Chimera (PROTAC) specifically targeting B-cell lymphoma extra large (Bcl-xL) to the celeblon (CRBN) E3 ligase for degradation, on combating the resistance and reducing the toxicity of bone growth caused by Hh inhibition.Methods: Fluorescence polarization, homogeneous time-resolved fluorescence (HTRF) assay, immunoblot, and immunoprecipitation (IP) were used to evaluate whether SIAIS361034 is an appropriate Bcl-xL PROTAC.Dual luciferase reporter assay, real-time quantitative PCR (RT-qPCR), depilatory model, and SmoA1 model were established to assess the effect of SIAIS361034 on the activity of Hh signaling pathway and its ability to overcome drug resistance in vitro and in vivo.Molecular mechanisms of SIAIS361034 for inhibiting Hh activity were demonstrated by dual luciferase reporter assay, immunoblot, and immunofluorescence staining.PET-CT and histopathology of bone tissues were used to assess the effects of SIAIS361034 on bone growth.Results: We observed that SIAIS361034 efficiently and selectively inhibits the activity of the Hh pathway in vitro and in vivo, by interrupting Bcl-xL/Sufu interaction, therefore, promoting the interaction of Sufu with Gli1.Moreover, SIAIS361034 possesses the ability of combating resistance to current Smo inhibitors caused by Smo mutations and Gli2 amplification and remarkably inhibits the growth of SmoA1 tumors in vivo.In contrast to von Hippel-Lindau (VHL) E3 ligase, our result further reveals little detectable expression of CRBN in two types of cells critical for bone development, human articular chondrocytes and human fetal osteoblastic cells.Moreover, treatment with SIAIS361034 results in no impairment on the bone growth of young mice, accompanying no alteration of the expression of Bcl-xL and Gli1 proteins.Conclusion: Our findings demonstrate that selectively targeting Bcl-xL by PROTAC is a promising strategy for combating resistance to Smo inhibitors without causing on-target drug toxicities of bone growth.
Negative Modulation of B Cell Activation by Melanocortin 1 Receptor Signaling Protects against Membranous Nephropathy
Authors: Bohan Chen, Xuejing Guan, William T. Gunning, Yan Ge, Amira F. Gohara, Lance D. Dworkin, Rujun Gong
Journal: Journal of the American Society of Nephrology (2022)

Background Emerging evidence suggests that the pituitary neuropeptide melanocortins—specifically, adrenocorticotropic hormone—offer a novel nonsteroidogenic therapeutic modality for membranous nephropathy (MN). However, the mechanism(s) of action remains elusive. Methods To investigate whether melanocortins modulate humoral immunity, we induced passive Heymann nephritis (PHN), a model of MN, in wild-type (WT) and melanocortin 1 receptor (MC1R) knockout (KO) rats. We treated the animals with melanocortin agents—repository corticotropin injection, the nonsteroidogenic pan-melanocortin receptor agonist [Nle 4 , DPhe 7 ]-α-melanocyte stimulating hormone, the selective MC1R agonist MS05, vehicle gel, or phosphate-buffered saline—and evaluated kidney function, histology, and molecular changes. Additional rats received adoptive transfer of syngeneic bone marrow-derived cells beforehand from WT or MC1R KO rats. Results KO of MC1R worsened PHN and this was associated with increased deposition of autologous immunoglobulin G (IgG) and complement C5b-9 in glomeruli and higher circulating levels of autologous IgG—evidence of a sensitized humoral immune response. Melanocortin therapy ameliorated PHN in WT rats, coinciding with reduced glomerular deposition of autologous IgG and C5b -9. The beneficial efficacy of melanocortins was blunted in KO rats but restored by adoptive transfer of syngeneic bone marrow-derived cells derived from WT rats. Mechanistically, MC1R was expressed in B lymphocytes and was negatively associated with B-cell activation. MC1R agonism triggered the expression of microphthalmia-associated transcription factor in activated B cells in a cAMP-dependent mode and also repressed the expression of interferon regulatory factor 4 (a lymphoid transcription factor essential for B-cell development and maturation), resulting in suppressed plasma cell differentiation and IgG production. Conclusions MC1R signaling negatively modulates B-cell activation and suppresses humoral immune responses in PHN, suggesting that MC1R signaling might offer a novel therapeutic target for MN.
Modulating the pharmacokinetic profile of Actinium-225-labeled macropa-derived radioconjugates by dual targeting of PSMA and albumin
Authors: Falco Reissig, Kristof Zarschler, Zbynek Novy, Milos Petrik, Katerina Bendova, Daniela Kurfurstova, Jan Bouchal, Marie-Charlotte Ludik, Florian Brandt, Klaus Kopka, Marta Khoylou, Hans-Jürgen Pietzsch, Marian Hajduch, Constantin Mamat
Journal: Theranostics (2022)

Small
Prothrombin Complex Concentrate and Cardiac Surgery
Authors: Hamnah Majeed, Haris Majeed
Journal: JAMA Surgery (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
The Crossroads of Cancer Epigenetics and Immune Checkpoint Therapy
Authors: Goran Micevic, Marcus W. Bosenberg, Qin Yan
Journal: Clinical Cancer Research (2022)

Abstract Immune checkpoint inhibitors (ICI) have significantly improved treatment outcomes for several types of cancer over the past decade, but significant challenges that limit wider effectiveness of current immunotherapies remain to be addressed. Certain “cold” tumor types, such as pancreatic cancer, exhibit very low response rates to ICI due to intrinsically low immunogenicity. In addition, many patients who initially respond to ICI lack a sustained response due to T-cell exhaustion. Several recent studies show that epigenetic modifiers, such as SETDB1 and LSD1, can play critical roles in regulating both tumor cell–intrinsic immunity and T-cell exhaustion. Here, we review the evidence showing that multiple epigenetic regulators silence the expression of endogenous antigens, and their loss induces viral mimicry responses bolstering the response of “cold” tumors to ICI in preclinical models. Similarly, a previously unappreciated role for epigenetic enzymes is emerging in the establishment and maintenance of stem-like T-cell populations that are critical mediators of response to ICI. Targeting the crossroads of epigenetics and immune checkpoint therapy has tremendous potential to improve antitumor immune responses and herald the next generation of sustained responses in immuno-oncology.
Cerenkov radiation-activated probes for deep cancer theranostics: a review
Authors: Nian Liu, Xinhui Su, Xiaolian Sun
Journal: Theranostics (2022)

Cerenkov radiation (CR) from radionuclides and megavoltage X-ray radiation can act as an in situ light source for deep cancer theranostics, overcoming the limitations of external light sources.Despite the blue-weighted emission and low quantum yield of CR, activatable probes-mediated CR can enhance the in-vivo diagnostic signals by Cerenkov resonance energy transfer and also can produce therapeutic effects by reactive species generation/drug release, greatly promoting the biomedical applications of CR.In this review, we describe the principles and sources of CR, construction of CR-activated probes and their application to tumor optical imaging and therapy.Finally, future prospects for the design and biomedical application of CR-activated probes are discussed.
Pulmonary drug delivery technology enables anakinra repurposing in cystic fibrosis
Authors: Matteo Puccetti, Marilena Pariano, Claudia Stincardini, Paulina Wojtylo, Aurelie Schoubben, Emilia Nunzi, Maurizio Ricci, Luigina Romani, Stefano Giovagnoli
Journal: Journal of Controlled Release (2022)
<i>LZTR1</i>Mutation Mediates Oncogenesis through Stabilization of EGFR and AXL
Authors: Aram Ko, Mohammad Hasanain, Young Taek Oh, Fulvio D'Angelo, Danika Sommer, Brulinda Frangaj, Suzanne Tran, Franck Bielle, Bianca Pollo, Rosina Paterra, Karima Mokhtari, Rajesh Kumar Soni, Matthieu Peyre, Marica Eoli, Laura Papi, Michel Kalamarides, Marc Sanson, Antonio Iavarone, Anna Lasorella
Journal: Cancer Discovery (2022)

Abstract LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase frequently mutated in sporadic and syndromic cancer. We combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations. Unbiased screens converged on EGFR and AXL receptor tyrosine kinases as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome. Pathogenic cancer-associated mutations of LZTR1 failed to promote EGFR and AXL degradation, resulting in dysregulated growth factor signaling. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system caused tumors in the peripheral nervous system including schwannoma-like tumors, thus recapitulating aspects of schwannomatosis, the prototype tumor predisposition syndrome sustained by LZTR1 germline mutations. Lztr1– and Cdkn2a-deleted tumors aberrantly accumulated EGFR and AXL and exhibited specific vulnerability to EGFR and AXL coinhibition. These findings explain tumorigenesis by LZTR1 inactivation and offer therapeutic opportunities to patients with LZTR1-mutant cancer. Significance: EGFR and AXL are substrates of LZTR1-CUL3 ubiquitin ligase. The frequent somatic and germline mutations of LZTR1 in human cancer cause EGFR and AXL accumulation and deregulated signaling. LZTR1-mutant tumors show vulnerability to concurrent inhibition of EGFR and AXL, thus providing precision targeting to patients affected by LZTR1-mutant cancer. This article is highlighted in the In This Issue feature, p. 517
MAFLD: How is it different from NAFLD?
Authors: Cameron Gofton, Yadhavan Upendran, Ming-Hua Zheng, Jacob George
Journal: Clinical and Molecular Hepatology (2022)

“Metabolic dysfunction-associated fatty liver disease (MAFLD)” is the term suggested in 2020 to refer to fatty liver disease related to systemic metabolic dysregulation. The name change from nonalcoholic fatty liver disease (NAFLD) to MAFLD comes with a simple set of criteria to enable easy diagnosis at the bedside for the general medical community, including primary care physicians. Since the introduction of the term, there have been key areas in which the superiority of MAFLD over the traditional NAFLD terminology has been demonstrated, including for the risk of liver and extrahepatic mortality, disease associations, and for identifying high-risk individuals. Additionally, MAFLD has been adopted by a number of leading pan-national and national societies due to its concise diagnostic criterion, removal of the requirement to exclude concomitant liver diseases, and reduction in the stigma associated with this condition. The current article explores the differences between MAFLD and NAFLD diagnosis, areas of benefit, some potential limitations, and how the MAFLD terminology has opened up new fields of research.
Depletion of gut microbiota improves the therapeutic efficacy of cancer nanomedicine
Authors: Ray Putra Prajnamitra, Yuan-Yuan Cheng, Chaw Yee Beh, Chien-Yi Lu, Jen-Hao Lin, Shu-Chian Ruan, Sheng-Lun Chen, Hung-Chih Chen, Ruey-Bing Yang, Patrick Ching-Ho Hsieh
Journal: Theranostics (2022)

Rationale: Gut microbiota plays a crucial role in cancer development and treatment.Studies show that although the gut microbiota is able to promote tumor growth, its presence also improves the efficacy of cancer treatment such as immunotherapy.To date, understanding of the potential impact of the gut microbiota on other treatment modalities such as cancer nanomedicine is still limited.In this study, we aimed to establish the relationship between gut microbiota and cancer nanomedicine, which can potentially open a new path in cancer treatment that combines gut microbiota modulation along with nanotherapeutics.Methods: Mice bearing 4T1 triple-negative breast cancer cells were subjected to gut microbiota modulation by antibiotics (ABX) treatment in the drinking water.Mice given normal water was used for control.The effects of ABX treatment towards gut bacteria was studied by RT-qPCR and 16S next generation sequencing of fecal samples.The mice were then subjected to liposomal doxorubicin (LipoDox) treatment and the amount of nanotherapeutics that accumulated in the tumors was quantified.For therapeutic efficacy, the mice were subjected to ABX treatment and given three injections of LipoDox or saline, while the tumor growth was monitored throughout.Results: Analysis of fecal bacterial content showed that ABX treatment resulted in depletion of gut microbiota.Quantification of LipoDox content revealed significantly increased accumulation in ABX tumor compared to control.Compared to LipoDox treatment alone, we found that combined gut microbiota depletion and LipoDox treatment resulted in augmented long-term anti-tumor efficacy and significantly improved median survival compared to LipoDox only (control vs ABX = 58.5 vs 74 days, p = 0.0002, n = 10 for both groups), with two mice surviving until the end of the experimental end point without experiencing relapse.We also identified the increase in vascular permeability of ABX-treated tumors correlated to for improved therapeutic efficacy and outcome. Conclusion:We showed that gut microbiota depletion led to enhanced tumor vascular permeability, which allowed a larger amount of LipoDox nanoparticles to accumulate in the tumor, leading to better long-term effects.Our results suggest that gut microbiota modulation may be exploited in combination with available nanomedicine-based therapeutics to improve cancer diagnosis, therapeutic efficacy and outcome.
Real‐Time Objective Evaluation of the Ischemic Stroke through pH‐Responsive Fluorescence Imaging
Authors: Shasha Yao, Chengbin He, Pengcheng Yuan, Xiaodan Xu, Xiaoxuan Zhou, Liyin Shen, Qiuhui Hu, Nigel K. H. Slater, Wenjing Sun, Youqing Shen, Hongjie Hu, Jianbin Tang
Journal: Advanced Healthcare Materials (2022)

A rapid and comprehensive assessment of ischemic stroke (IS) is critical for clinicians to take the most appropriate treatment. Currently, IS assessment is mainly carried out by computed tomography and magnetic resonance imaging in combination with observing the clinical symptoms and inquiring about contraindications. However, they cannot diagnose pathological conditions and judge the microenvironment in real-time. Near-infrared fluorescence imaging has advantages for IS imaging, such as high sensitivity, high spatiotemporal resolution, and straightforward real-time operation. Herein, a pH-responsive fluorescent liposomal probe (BOD@Lip) is prepared for in vivo real-time visualization of the degree of IS based on the different acid microenvironments in the progression of the disease. The fluorescence imaging with BOD@Lip shows the degree of IS, and the correlation between fluorescence signals and the neurological deficit scores is established for the first time. This work provides a new method to objectively evaluate the degree of IS through a visualized route and a new insight into the relationship between the acidic microenvironment and the progression of IS.
Signatures of EMT, immunosuppression, and inflammation in primary and recurrent human cutaneous squamous cell carcinoma at single-cell resolution
Authors: Xin Li, Shuang Zhao, Xiaohui Bian, Lining Zhang, Lixia Lu, Shiyao Pei, Liang Dong, Wensheng Shi, Lingjuan Huang, Xiyuan Zhang, Mingliang Chen, Xiang Chen, Mingzhu Yin
Journal: Theranostics (2022)

Rationale:The recurrence of cutaneous squamous cell carcinoma (cSCC) after surgery is associated with the reprogramming of the tumor microenvironment (TME), and remains a key factor affecting its outcomes.Methods: We employed single-cell RNA sequencing (scRNA-seq) to examine the dynamic changes in epithelial cells, T cells, myeloid cells, and fibroblasts between primary and recurrent cSCC.Cell clustering, cell trajectory, cell-cell communication, and gene set enrichment analysis were used to investigate the TME heterogeneity between primary and recurrent cSCC.Gene expression differences were monitored by IHC staining.Results: We examined the immunosuppressed microenvironment in recurrent cSCC, which exhibited a T cell-excluded and SPP1 + tumor-associated macrophages (TAMs)-enriched status.In recurrent cSCC, CD8 + T cells showed high exhaustion and low inflammatory features, while SPP1 + TAMs displayed global pro-tumor characteristics, including decreased phagocytosis and inflammation and increased angiogenesis.Furthermore, the subgroups of SPP1 + TAMs harbored distinct functions.SPP1 + CD209 high TAMs showed features of phagocytosis, while SPP1 + CD209 low TAMs tended to have a high angiogenic ability.A subpopulation of tumor-specific keratinocytes (TSKs) showed significant epithelial-mesenchymal transition (EMT) features in recurrent cSCC, probably due to their active communication with IL7R + cancer-associated fibroblasts (CAFs).Moreover, we found that the pleiotropic growth factor/cytokine Midkine (MDK) could provoke different cell-cell interactions in cSCC with distinctive staging.In primary cSCC, MDK was highly expressed in fibroblasts and could promote their proliferation and block the migration of tumor cells, while in recurrent cSCC, the high expression of MDK in TSKs promoted their proliferation and metastasis. Conclusion:Our study provides insights into the critical mechanisms of cSCC progression, which might facilitate the development of a powerful approach for the prevention and treatment of cSCC recurrence.
Appraising the Quality of Development and Reporting in Surgical Prediction Models
Authors: Jayson S. Marwaha, Hao Wei Chen, Karl Habashy, Jeff Choi, David A. Spain, Gabriel A. Brat
Journal: JAMA Surgery (2022)

This cross-sectional study uses the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis reporting guideline to assess 120 published studies about surgical prediction models.
Zwitterionic Polysaccharide‐Based Hydrogel Dressing as a Stem Cell Carrier to Accelerate Burn Wound Healing
Authors: Qingyu Yu, Hong Sun, Zhiwei Yue, Chaojie Yu, Lijie Jiang, Xiaoru Dong, Mengmeng Yao, Mingyue Shi, Lei Liang, Yizao Wan, Hong Zhang, Fanglian Yao, Junjie Li
Journal: Advanced Healthcare Materials (2022)

Stem cell therapy integrated with hydrogels has shown promising potential in wound healing. However, the existing hydrogels usually cannot reach the desired therapeutic efficacy for burn wounds due to the inadaptability to wound shape and weak anti-infection ability. Moreover, it is difficult to improve the environment for the survival and function of stem cells under complicated wound microenvironments. In this study, an injectable and self-healing hydrogel (DSC), comprising sulfobetaine-derived dextran and carboxymethyl chitosan, is fabricated through a Schiff-base reaction. Meanwhile, the DSC hydrogel shows high nonfouling properties, including resistance to bacteria and nonspecific proteins; moreover, the prepared hydrogel can provide a biomimetic microenvironment for cell proliferation whilst maintaining the stemness of adipose-derived stem cells (ADSCs) regardless of complex microenvironments. In burnt murine animal models, the ADSCs-laden hydrogel can significantly accelerate wound healing rate and scarless skin tissue regeneration through multiple pathways. Specifically, the ADSCs-laden DSC hydrogel can avoid immune system recognition and activation and thus reduce the inflammatory response. Moreover, the ADSCs-laden DSC hydrogel can promote collagen deposition, angiogenesis, and enhance macrophage M2 polarization in the wound area. In summary, sulfobetaine-derived polysaccharide hydrogel can serve as a versatile platform for stem cell delivery to promote burn wound healing.
Efficacy of a Connected Insulin Pen Cap in People With Noncontrolled Type 1 Diabetes: A Multicenter Randomized Clinical Trial
Authors: Fernando Gomez-Peralta, Cristina Abreu, Elsa Fernández-Rubio, Laura Cotovad, Pedro Pujante, Sonia Gaztambide, Diego Bellido, Edelmiro Menéndez Torre, Santiago Ruiz-Valdepeñas, Hugo Bello, Xoan Valledor, Jesús Pérez-González, Luis Ruiz-Valdepeñas
Journal: Diabetes Care (2022)

OBJECTIVE To assess the efficacy of the insulin pen cap Insulclock on improving glycemic control, treatment adherence, and user satisfaction in people with type 1 diabetes. RESEARCH DESIGN AND METHODS This multicenter, open-label, randomized controlled trial comprised a 4-week run-in phase and a 6-week double-arm phase in which participants were randomly assigned into an active or masked mode. RESULTS Fifty-five participants were evaluable (active group, n = 26, masked group, n = 29). The increase in time in range was higher in the active versus masked group (5.2% vs. −0.8%; P = 0.016). The active group showed a higher reduction in mean glucose, glucose management indicator, time above range, and high blood glucose index. On-time insulin doses increased in the active group and decreased in the masked group. CONCLUSIONS Insulclock system use was associated with improved glycemic control, glycemic variability, hyperglycemia risk, and treatment adherence in people with uncontrolled type 1 diabetes.